studies

274A AASLD ABSTRACTS HEPATOLOGY, October, 2015
The following authors have nothing to disclose: Maria E. Lozada, Jonggi Choi,
Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H. Giama, Steven Alberts
128
Trends in the burden of cirrhosis and hepatocellular carcinoma
by underlying liver disease in US Veterans from
2001-2013
Lauren A. Beste 2 , Steven Leipertz 2 , Pamela Green 2 , Jason A. Dominitz
2,1 , David Ross 3 , George N. Ioannou 2,1 ; 1 University of Washington,
Seattle, WA; 2 Veterans Affairs Puget Sound Healthcare
System, Seattle, WA; 3 Office of Public Health, Department of Veterans
Affairs, Washington, D.C., DC
Background & Aims Cirrhosis and hepatocellular carcinoma
(HCC) are predicted to increase in the U.S. but the accuracy
of prior forecasts and the contributions from various etiologies
remain unclear. We aimed to determine the burden of
cirrhosis and HCC according to underlying etiology from
2001-2013. Methods We developed a national retrospective
cohort of Veterans Affairs (VA) patients diagnosed with cirrhosis
(n=129,998) or HCC (n=21,326) from 2001-2013.
We used laboratory results, ICD-9 codes, and biometrics to
identify underlying etiologies. Results In 2013, VA provided
care to 5,720,614 individuals, of whom 60,553 (1.06%) had
cirrhosis and 7,670 (0.13%) had HCC. Hepatitis C virus (HCV)
was present in an increasing proportion of cirrhosis and HCC
between 2001-2013, reaching 48% of cirrhosis cases and
deaths and 67% of HCC cases and deaths by 2013. Cirrhosis
prevalence nearly doubled from 2001-2013 (664 to 1058
per 100,000 enrollees), driven by HCV and nonalcoholic fatty
liver disease (NAFLD). Cirrhosis incidence ranged from 159
to 193 per 100,000 patient-years. Deaths in patients with
cirrhosis increased from 83 to 126 per 100,000 patient-years,
largely driven by HCV. HCC incidence increased 2.5-fold from
17 to 45 per 100,000 patient-years. HCC mortality tripled
from 13 to 37 per 100,000 patient-years, driven overwhelmingly
by HCV with much smaller contributions from NAFLD and
alcoholic liver disease. Conclusions Cirrhosis prevalence and
mortality and HCC incidence and mortality increased from
2001-2013 driven by HCV with a smaller contribution from
NAFLD. If current trends continue, cirrhosis prevalence will
peak in 2021. Healthcare systems will need to accommodate
rising numbers of patients with cirrhosis and HCC.
INCIDENCE OF HCC IN THE VETERANS AFFAIRS HEALTHCARE
SYSTEM 2002-2012, BY UNDERLYING LIVER DISEASE
Disclosures:
Jason A. Dominitz - Employment: Department of Veterans Affairs; Grant/Research
Support: Gilead Pharmaceuticals
The following authors have nothing to disclose: Lauren A. Beste, Steven Leipertz,
Pamela Green, David Ross, George N. Ioannou
129
Multi-platform analysis of Telomerase Reverse Transcriptase
(TERT) gene alterations in Hepatocellular Carcinoma
(HCC)
Renumathy Dhanasekaran 1 , Kyle Covington 2 , Jennifer Watt 2 ,
Andrew D. Cherniack 3 , Daniel R. O’Brien 4 , Ju-Seog Lee 5 , Chad
Creighton 2 , Donna M. Munzy 2 , Lewis R. Roberts 1 , David A.
Wheeler 2 ; 1 Gastroenterology and Hepatology, Mayo Clinic, Rochester,
MN; 2 Baylor College of Medicine, Houston, TX; 3 Broad
Institute of MIT and Harvard, Cambridge, MA; 4 Mayo Clinic, Rochester,
MN; 5 The University of Texas MD Anderson Cancer Center,
Houston, TX
Background: Telomerases are enzymatic protein complexes
which maintain telomere length and play an important role in
cancer cell immortalization. Mechanisms of TERT gene activation
and clinical associations of TERT gene alterations in
HCC are not completely understood. Methods: We used data
from TCGA analysis of HCC primary tumor from 192 patients.
Germline DNA from blood or benign surrounding liver was
used as reference. Mutational, copy number, mRNAseq and
viral genomic integration analyses were performed. Results:
The TERT gene was found to be significantly overexpressed
in HCC tumor tissue when compared to benign surrounding
liver (pA (C228T) and 1,295,250 G>A (C250T)) were found.
The majority of tumors had the C288T mutation (92.1%) and
six (7.9%) tumors had the C250T mutation. Patients with TERT
promoter mutation were older (p=0.03) and predominantly
male (p=0.02). Patients with TERT promoter mutation were
more likely to have hepatitis C than no mutation (33% vs 10%;
p=0.02). In contrast, patients with TERT promoter mutation
were less likely to have hepatitis B than no mutation (14% vs.
27%; p=0.05). Also, patients with TERT promoter mutation
had worse survival than patients without the mutation (3 year
survival 59% vs. 39%; p=0.02). Further, we report here the first
case of a germline mutation in the TERT promoter in HCC in a
30 year old male who did not have any risk factors for HCC.
Copy number analyses showed TERT gene amplification in
7% of tumor samples; TERT was the fourth most common gene
found to be amplified in HCC. There was significant correlation
between TERT gene amplification and TERT mRNA overexpression.
In the subset of patients with HBV infection, the integration
of HBV viral genome into TERT promoter region was identified
in 13.6% (6/44) of patients and this was the most common site
of recurrent HBV integrations. Conclusion: This is the first comprehensive
multi-platform analysis of the various mechanisms of
TERT gene alterations in HCC and their association with patient
outcomes. TERT promoter mutations were found to be the most
common somatic mutation in HCC and were associated with
poor survival. We identify TERT promoter somatic mutations,
TERT gene amplification and HBV integrations into the TERT
promoter region as various mechanisms of TERT gene alterations.
Also, we report here the first case of germline mutation
of the TERT promoter gene in HCC, possibly resulting in an
inherited predisposition to HCC.